After osmotic lysis, erythrocyte membranes are able to recover impermeability in certain conditions. Many of the factors that induce resealing have been determined. It is therefore worthwhile to undertake a study of the structural rearrangements that occur in the membrane in going from the permeable to the impermeable state. A simple hypothesis is proposed, based on the observation of distinct permeability barriers for cations and macromolecules, which is capable of experimental testing. The macromolecule barrier is proposed to be a function of an intact lipid bilayer, while cation resealing should require protein-lipid or protein-protein reorganization. This will be tested by observing the effect of compounds that alter lipid fluidity on resealing; by chemical cross-linking studies of the topological orientation of protein-lipid and protein-protein complexes in the membrane; and by assaying the influence of site-specific labeling modifications such as enzymic digestion, specific for one class of membrane component or individual components, on the recovery of the permeability barriers. Emphasis will be placed on the role of (Na,K) ATPase in this process.